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Biomedical subjects

B G Katzung

Publications and source records attributed to B G Katzung.

At least 19 recordsLinked to original sources
PubMed1987

Use-dependence of ryanodine effects on postrest contraction in ferret cardiac muscle.

During an investigation of the effect of ryanodine on contractions in cardiac muscle, it was found that long rest periods removed all or most of the drug's effect. Therefore, we studied the kinetics of block development and recovery from block produced by low concentrations of ryanodine (1-100 pM) on the postrest contractions of ferret papillary muscle. At 100 pM, ryanodine depressed steady-state contraction amplitude slightly (4.2 +/- 1.1% mean +/- SEM, n = 10) but strongly inhibited (40-80%) the first contraction (postrest contraction) elicited on restimulation of the preparation after rest periods of 1 second to 5 minutes. Under control conditions, the nearly maximal potentiation of the twitch occurring after a standard test rest period (30 seconds of rest) was not affected by a preceding conditioning rest of up to 20 minutes. In the presence of 100 pM ryanodine, a conditioning rest increased the amplitude of the twitch elicited after a test rest, and the test rest contraction recovered toward control (drug-free) amplitude monoexponentially (time constant, 582 +/- 105 seconds). Block of postrest contraction could be reinduced by stimulation and occurred faster when higher rates were used (time constants, 758 seconds at 1 Hz and 107 +/- 26 seconds at 3 Hz). Since rest potentiation of twitch tension is believed to be mostly dependent on extra calcium released from the sarcoplasmic reticulum, the results suggest that the ryanodine-induced blockade of calcium release from the sarcoplasmic reticulum is use-dependent and recovers during diastole.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1986

Biphasic contractions induced by milrinone at low temperature in ferret ventricular muscle: role of the sarcoplasmic reticulum and transmembrane calcium influx.

The effects of milrinone were studied in ferret papillary muscle stimulated at various rates and temperatures from 23 degrees to 36 degrees C. In voltage-clamp experiments, 50 micrograms/ml (0.237 mM) milrinone induced a 2.1-fold increase in calcium current at 28 degrees or 36 degrees C. At 50 micrograms/ml, milrinone transiently increased contractility in all muscles at 28 degrees C, but its steady-state effect was either increased (+50%) or decreased (-24.7%) steady-state twitch amplitude. A negative inotropic effect always occurred below 27 degrees C. Milrinone decreased the total twitch duration and split the twitch into two components (P1 and P2) in the absence of any evidence of aberrant conduction. Increasing milrinone concentration from 50 to 300 micrograms/ml decreased P1 and increased P2. Ryanodine (100 mM) or caffeine (10 mM) suppressed P1. Contractions elicited after 30 seconds of rest were also biphasic in the presence of milrinone, but not in its absence. P2 of post-rest contraction was increased by caffeine or calcium (10 mM) and decreased by cobalt (2 mM) when drugs were applied at the beginning of the rest. Ryanodine and caffeine also suppressed P1 of post-rest contraction. The evidence suggests that P1 may be caused by Ca release from the sarcoplasmic reticulum and P2 by increased Ca influx during the action potential via the calcium channel. It is also suggested that P2 may be present under control conditions, but to a lesser extent, and masked by a large P1.

Action Potentials↗
PubMed1985

Effects of sodium substitutes on transient inward current and tension in guinea-pig and ferret papillary muscle.

We used ouabain-treated guinea-pig and ferret papillary muscles to study transient inward current (Iti), after-contractions, and tonic tension development during voltage-clamp pulses. Li, sucrose and choline were used isosmotically as Na substitutes to evaluate the effect of altering the Na equilibrium potential. We were unable to detect outward Iti at any potential up to +30 mV in normal or Na-depleted solutions. However, reduction of Na had a biphasic effect on Iti, initially increasing it and then reducing it at all clamp potentials from -50 to +20 mV. After-contractions were also initially increased and, in sufficiently Na-depleted solutions, decreased by reduction of extracellular Na. However, the peak in the after-contraction always occurred later than the increase in Iti and frequently coincided with the maximum suppression of the current. Complete suppression of after-contractions was not often achieved and always required more complete Na replacement than Iti suppression. Tonic tension responses were reduced by Na replacement, usually in synchrony with the reduction of Iti. The responses of Iti to Na replacement are consistent with a model of electrogenic Na-Ca exchange over the potential range positive to -50 mV. The responses deviate from the predictions of the model at more negative potentials. The results are consistent with the previous proposal that oscillatory changes in internal free Ca concentration underlie both Iti and after-contractions.

Action Potentials↗
PubMed1985

Amrinone effects on electromechanical coupling and depolarization-induced automaticity in ventricular muscle of guinea pigs and ferrets.

The effects of the cardiotonic agent, amrinone (0.05-4 mM), on electrical and mechanical activities of ferret and guinea-pig papillary muscles were studied using current and voltage clamp (single sucrose gap) techniques. In current clamp studies, amrinone increased, in a dose-dependent manner, contractile force elicited by action potential in both species. Depolarization-induced automaticity was facilitated in ferret muscles at all maximum diastolic potentials between -70 and -15 mV. Facilitation of automaticity in guinea-pig muscles occurred only at potentials more negative than -35 mV and was suppressed at more positive potentials. Cimetidine (10 microM) partially reversed the effects of amrinone on automaticity in both species. In voltage clamp studies, amrinone increased the slow inward current. Steady-state outward current was increased in guinea-pig but not in ferret muscles. A dual effect of amrinone on tension was observed. Amrinone was found to increase phasic tension of ferret papillary muscles only for depolarizations lasting less than 250 to 300 msec. For longer depolarizations, amrinone decreased the phasic tension (in a dose-dependent manner), whereas the tonic tension was not modified. The decrease as well as the increase in tension was associated with an increase of the slow inward current. The results suggest that amrinone may be arrhythmogenic and may have an intracellular action at the sarcoplasmic reticulum level (partial inhibition) in addition to its action on the calcium current.

Action Potentials↗
PubMed1984

Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by amiodarone.

The electrophysiological effects of amiodarone were studied in guinea pig papillary muscle by means of the single sucrose gap voltage clamp technique. The first time derivative of the upstroke of the action potential was measured as an indicator of the sodium current. The preparations were not voltage clamped during the action potential upstroke. Acute effects of amiodarone (4.4 X 10(-5) M and 8.8 X 10(-5) M; six experiments each) and effects of chronic administration at a single dose level (nine experimental vs. eight control animals) were studied. Results were qualitatively the same for all experimental conditions, and concentration dependent in the acute studies. Amiodarone caused marked use-dependent depression of the first time derivative of the upstroke of the action potential during stimulus trains. For example, at normal resting potential, chronic amiodarone treatment reduced the first time derivative of the upstroke of the action potential of the 16th beat of trains of cycle length 300 msec to 70 +/- 15% (mean +/- SD) of the initial value. This blocking effect was accentuated at more depolarized holding potentials and reduced at hyperpolarized holding potentials. Reduction of the first time derivative of the upstroke of the action potential was found to depend upon sodium channel inactivation. For all experiments, the mean normalized first time derivative of the upstroke of the action potential following a 1-second clamp in the -20 to +20 mV range was 0.92 +/- 0.08 in the control condition and 0.66 +/- 0.20 in the presence of amiodarone (less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1984

Effects of diltiazem on transmembrane potential and current of right ventricular papillary muscle of ferrets.

We studied the effects of diltiazem on electrical properties of isolated ferret right ventricular papillary muscles. By using standard microelectrode recording techniques and current clamp and voltage clamp protocols (single sucrose gap method), we measured action potential variables, depolarization-induced automaticity, slow (or second) inward current (Isi) and time-dependent and isochronal (1 sec) outward current. Resting potential was unaffected at all concentrations studied (from 2 nM-11 microM). At concentrations below 2 microM and at slow rates of stimulation (0.5 Hz), a small reduction of overshoot and prolongation of the action potential duration at 80% of full repolarization were observed. At concentrations of 2.2 microM or greater, marked use-dependent reductions of overshoot and plateau duration were observed that reversed with rest. Depolarization-induced automaticity was selectively suppressed at less negative diastolic potentials. In voltage clamp studies, peak Isi was markedly diminished over the concentration range studied (50% inhibitory concentration, 0.5 microM), but the current-voltage relation for Isi was not shifted on the voltage axis. The diminution in Isi was strongly use-dependent and voltage-dependent. Diltiazem (1.1 microM) had small effects on outward currents. Steady-state (isochronal) outward current and the time-dependent outward current were both reduced by 10 to 20% over the entire voltage range. Diltiazem is a potent inhibitor of the slow inward current in ventricular muscle. Its interaction with slow channel receptors appears to be strongly modulated by the state of the channels.

Action Potentials↗
PubMed1983

Diltiazem and verapamil preferentially block inactivated cardiac calcium channels.

Diltiazem has been proposed to act by blocking calcium channels of cardiac and smooth muscle since it has pharmacological [12-14] and clinical [10] effects that resemble those of verapamil, an agent that has been shown to block these channels [3]. However, block of the slow inward current by diltiazem has not been directly demonstrated. In fact, it has been suggested that diltiazem has an entirely different mechanism of action [7]. We therefore studied the blocking effects of diltiazem and verapamil on cardiac calcium channels by measuring the slow inward current in voltage-clamped ferret myocardium. Both drugs blocked the slow inward current in a use-dependent fashion, i.e. the block was enhanced by increased frequency of activating clamps and by more positive holding potentials. However, we found that short single activating clamps resulted in minimal block, whereas prolonging the clamp step progressively enhanced the blockade. Thus, a single long clamp caused as much blockade as a train of shorter pulses. These results demonstrate that diltiazem and verapamil block the slow inward current by binding to calcium channels in a state-dependent fashion, i.e. inactivated channels have a high affinity for the drugs, while rested and open channels have a lower affinity.

Animals↗
PubMed1982

Biphasic effects of acetylstrophanthidin on automaticity in guinea pig ventricular muscle.

The effects of acetylstrophanthidin (AS) on depolarization-induced automaticity and contractility of guinea pig papillary muscle were studied in a single sucrose gap chamber with microelectrode and current-clamp techniques. The concentration used, 1.4-1.8 microM, never induced automaticity in preparations at their normal resting potential. Twenty min after superfusion with AS, action potential duration (APD) was prolonged and the force of contraction increased. These were associated with an increase in slope of phase 4 depolarization and an increase in the membrane resistance (Rm) of muscles depolarized with small constant current pulses. With longer (50-80 min) periods of AS superfusion, APD became shorter, Rm decreased to less than predrug values, and in depolarized preparations, the slope of phase 4 decreased. Contractility remained unchanged throughout this second phase. All of these effects were fully reversible upon 60 min of superfusion with AS-free Tyrode solution. We suggest that the biphasic effects of AS on the automaticity of depolarized ventricular muscle cells are caused by an initial decrease followed by a later increase in transmembrane potassium conductance.

Animals↗
PubMed1982

Do calcium-dependent ionic currents mediate ischemic ventricular fibrillation?

Calcium ions mediate the adverse effects of myocardial ischemia and have been implicated in the genesis of arrhythmias. Calcium influx blocking drugs protect against early ventricular arrhythmias during experimental coronary occlusion, and recent studies suggest that this effect is at least partly due to inhibition of myocardial cell calcium influx. Most of the pharmacologic maneuvers used to simulate acute ischemic arrhythmias in vivo also produce intracellular calcium overload. Production of calcium overload in small myocardial cell clusters causes fibrillatory electrical and mechanical activity similar to that recorded from fibrillating hearts. Fibrillation in these cell clusters is mediated not by reentrant conduction, but by the same subcellular processes that give rise to depolarizing afterpotentials and abnormal automaticity. Agents favoring calcium influx, such as beta adrenergic agonists, accentuate these processes, while agents that depress calcium influx inhibit them. Although the relation of these experimental models to clinical ischemic arrhythmias has not been fully delineated, calcium influx blocking drugs may prove useful in reducing the incidence of sudden cardiac death.

Animals↗
PubMed1982

Voltage-clamp studies of transient inward current and mechanical oscillations induced by ouabain in ferret papillary muscle.

1. We studied the effects of a toxic concentration of ouabain on transmembrane electrical activity and on mechanical behaviour of right ventricular papillary muscles from ferrets in a single sucrose-gap using current clamp and voltage clamp.2. Ouabain (1.4-1.8 muM) induced oscillatory after-potentials and after-concentrations in current-clamp experiments. Voltage clamp showed that the oscillatory after-potential was caused by a transient inward current, similar to that in Purkinje fibres.3. The transient current had a sigmoidal dependence on the preceding (activating) voltage step V1, with a treshold around -13 mV and a plateau between +10 and 20 mV. There was a decline in current amplitude for more positive clamps. When activated by a fixed V1 voltage step, and measured at different repolarization levels V2, the transient current manifested an inverse dependence on V2 between -50 and -10 mV. No outward transient current could be detected. Total replacement of Na in the bathing medium by Tris or by sucrose abolished the transient current.4. Ouabain caused an increase of phasic (twitch) tension responses to voltage steps at all potentials without shifting the curve relating these variables on the voltage axis. The drug evoked an even greater increase in the tonic tension responses.5. After prolonged exposure, oscillatory mechanical responses were frequently recorded during positive voltage steps. Unlike the after-contraction, these mechanical fluctuations were not consistently damped and were not accompanied by detectable synchronous current fluctuations. Catecholamines and dibutyryl cyclic AMP markedly reduced the amplitude of the tonic contraction and the mechanical oscillations but increased their frequency. Caffeine had no effect on the tonic contraction amplitude but abolished the fluctuations.6. These results support the proposal that Ca is transiently released from the overloaded sarcoplasmic reticulum in ouabain-intoxicated muscle and may evoke oscillatory responses in nearby contractile fibrils. When these transient increases of sarcoplasmic free Ca are large enough, they may induce the transient transmembrane current described above.

Animals↗
PubMed1981

Cesium blockade of delayed outward currents and electrically induced pacemaker activity in mammalian ventricular myocardium.

The effects of Cs+, 5-25 mM, were studied in cat and guinea pig papillary muscles using voltage clamp and current clamp techniques. In solutions containing normal K+, the major effects of Cs+ were depolarization of the resting potential and reduction of the delayed outward current (ixl) between -80 and -20 mV. Both inward and outward portions of the isochronal current voltage relation (l-s clamps) were reduced by extracellular Cs+. This resulted in a substantial reduction of inward rectification and, by subtraction from the normal I-V relationship, the definition of a Cs+-sensitive component of current. Under current clamp conditions, 5-10 mM Cs+ produced a dose-dependent slowing of repetitive firing induced by depolarization. At higher concentrations (25 mM) the resting potential was depolarized and repetitive activity could not be induced by further depolarization. However, release of hyperpolarizing pulses was followed by prolonged bursts of repetitive action potentials, suggesting partial reversal of blockade or participation of another pacemaker process. The experimental results and a numerical simulation show that under readily attainable conditions, reduction in an outward pacemaker current may slow pacemaker activity.

Action Potentials↗
PubMed1980

Physiological role of endogenous amines in the modulation of ventricular automaticity in the guinea-pig.

1. Current-clamp experiments were carried out with guinea-pig papillary muscles to determine the dependence of depolarization-induced automaticity on endogenous catecholamines. 2. Catecholamine depletion was produced by pre-treatment of animals with 6-hydroxydopamine and confirmed by fluorimetric assay of right ventricular tissue. Papillary muscles from depleted animals demonstrated a marked suppression of depolarization-induced automaticity for maximum diastolic potentials less negative than -55 mV. This suppression was completely reversed by noradrenaline but not by tyramine. 3. In normal tissue, noradrenaline and tyramine had much smaller effects on automaticity arising from maximum diastolic potentials negative to -55 mV than on repetitive activity arising positive to this level. 4. L-propranolol in concentrations of 2-3 x 10(-7) M reduced repetitive activity in the less negative range of maximum diastolic potential. No evidence of direct membrane depression was observed at these doses and the effect was reversed by application of noradrenaline. 5. D-propranolol, the isomer with much lower beta-receptor blocking potency, required twentyfold higher concentrations to depress automaticity and this was accompanied by evidence of direct membrane depression, i.e. reduction of upstroke velocity of action potentials. 6. These results show that automaticity induced in guinea-pig papillary muscles by depolarization positive to -55 mV is strongly dependent upon endogenous catecholamines. 7. The hypothesis that endogenous catecholamines facilitate depolarization-induced automaticity through an increase in calcium conductance was modelled using numerical techniques. It was found that changes in calcium conductance caused changes in the model which closely parallelled the experimental effects of catecholamine depletion and beta-blockade. The effects of changes in delayed rectification in the model did not accurately reproduce the experimental results.

Animals↗